The present invention generally relates to drug diffusion polymer systems and more particularly, to compositions and devices incorporating such compositions for sustained release of drugs and to methods of making such compositions and devices.
Compositions and devices for the delivery of a drug to an aqueous body environment during a prolonged period of time are well known in the art. These often comprise an admixture of a physiologically acceptable polymer and a drug. In addition to the drug, other additives may be included in the composition to provide drug release. The release of the drug is typically a function of the composition; the device often having a separate utility even though the drug release may be particularly complimentary thereto. As used herein, an aqueous body environment is a subcutaneous, percutaneous or interior region of an animal or human having a body fluid or water presence sufficient for solubilizing and diffusing a drug.
One type of drug release or diffusion composition comprises an imperforate polymer matrix containing a dissolved drug which is permeable through the polymer matrix by diffusion. Such a diffusion system requires a unique matching of polymer and drug properties.
Another type of composition involves dispensing of the drug from a biodegradable polymeric material as described in U.S. Pat. Nos. 3,887,699 and 4,148,871. The degrading polymer component in such a composition burdens the user's system.
It is also known to dispense drugs from porous polymeric compositions characterized by interconnected cells which contain the solid or liquid drug in depots as disclosed in U.S. Pat. No. 4,702,917. The fluid or water of the body environment dissolves the drug and forms a tortuous diffusion pathway. These compositions usually require the use of a relatively large proportion of drug in order to assure porosity. Also, they tend to have an undesirably high diffusion rate, and devices employing such compositions may become prematurely ineffective and require replacement.
Polymeric compositions containing solid drug depots are also used to provide osmotic bursting compositions as disclosed in U.S. Pat. Nos. 3,923,939 and 4,177,256. The water of the body environment is imbibed osmotically into the depots in a serially inward direction to dissolve the drug within the depots and to generate sufficient pressure therein to burst adjacent polymer layers. This release technique imposes particular physical properties such as tensile and modulus characteristics upon the polymer materials which are useful.
Drug diffusion polymeric systems or compositions may be used to form the device itself, especially when the device has no separate or additional utility other than delivery of the drug to the system. More often, the device has a separate utility and the composition may be applied to the device as a coating or otherwise be associated with the device in order to provide a composition or drug delivery surface of predetermined area which is exposed to the body environment. For example, the use of catheters, percutaneous access devices such as feeding devices and peritoneal dialysis devices is associated with a high risk of infection. This risk may be substantially reduced by incorporating a drug release composition into the device with a sustained release of drug to the device surface and body environment of an antibiotic.
The use of drug release compositions as the primary material of construction in such devices has been substantially hindered, if not impeded, by the adverse effects of manufacturing processes and conditions upon drugs and diffusion additives. Problems encountered include drug degradation and drug and/or additive interference with the polymerizing or curing of the primary constructional polymer by the drug and/or additive.
As used herein, the term "drug" broadly includes physiologically or pharmacologically active substances for producing a localized effect at the administration site or a systemic effect at a site remote from the administration site. Such drugs include inorganic and organic compounds, for example, drugs which act on the central nervous system such as hypnotics and sedatives, psychic energizers, tranquilizers, anticonvulsants, muscle relaxants and anti-parkinson agents, antipyretics and anti-inflammatory agents, local anesthetics, anti-spasmodics and anti-ulcer agents, prostaglandins, antibiotics, hormonal agents, estrogenic steroids, progestational steroids, such as for contraceptive purposes, sympathomimetic drugs, cardiovascular drugs, diuretics, antiparasitic agents, hypoglycemic drugs and ophthalmic drugs. The antibiotics are of particular importance and application herein. Illustrative water-soluble antibiotics include, without limitation, cephalothin, neomycin, ampicillin, tobramycin, kanamycin, tetracycline, lincomycin, nitrofurantoin, bacitracin, and nystatin. The drug should be a solid or convertible to solid form by reaction, such as salt formation and crystallization.